Fetal alcohol spectrum disorder (FASD) is a prevalent condition (2-5% in the U.S.) characterized by learning and memory alterations. Studies have shown that disruptions in the function of the hippocampus play a role in the pathophysiology of FASD. Our long-term goal is to identify the molecular and cellular mechanisms responsible for the effects of ethanol on the developing hippocampus. During the extension period of this Merit award, we propose to characterize ethanol?s effect on GABAergic hippocampal interneurons and to determine if the presence of a BDNF polymorphism increases vulnerability of the developing hippocampus to ethanol-induced damage. Aim #1 will test the the hypothesis that developmental ethanol exposure persistently damages interneurons in the dentate gyrus. The flow of information into the hippocampal formation is gated by a diverse group of GABAergic interneurons whose migration and integration into the network take place during the rodent equivalent to the 2nd and 3rd trimesters of human pregnancy. We found that ethanol exposure of mice during the equivalent to these trimesters dramatically reduces the number of dentate gyrus interneurons. We will explore the mechanism responsible for this effect and characterize the morphology and function of surviving interneurons using electrophysiological and optogenetic techniques. We will assess whether ethanol exposure alters spatial memory and attempt to correct these behavioral deficits by stimulating interneurons using optogenetics or DREADDs. Aim 2 will test the hypothesis that a BDNF polymorphism (Met68BDNF), that disrupts intracellular trafficking of immature BDNF and reduces activity-dependent release of this factor, increases the susceptibility of developing hippocampal neurons to ethanol-induced damage. We will assess the impact of developmental ethanol exposure on the morphology and function of hippocampal neurons in wild-type and Met68BDNF mice. We will investigate whether hippocampal-dependent behaviors are more severely affected by developmental ethanol exposure in Met68BDNF mice. These studies will lay the foundation for future translational studies on whether this polymorphism modulates the severity of FASD in humans.